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• Epigenetic age deceleration reflects fitness improvements following a six-month endurance exercise intervention

  Epigenetic clocks are emerging as promising biomarkers of biological aging, yet their sensitivity to short-term interventions remains unclear. This pilot study investigates whether the GrimAge clock can capture the effects of a six-month cycling-based endurance exercise training intervention, with cardiorespiratory fitness (VO₂ max) and body composition as primary outcomes. We enrolled 42 adults aged 35-65, of whom 38 completed the study and 33 adhered to the protocol (>66% adherence). Participants demonstrated significant improvements in VO₂ max (+20%, P < 0.001) and body composition (P < 0.001). High-quality epigenetic data preprocessing yielded highly reproducible GrimAge estimates (< 2 months measurement error), which strongly correlated with chronological age (R² = 0.86, P < 0.001). On average, GrimAge decreased by 7.44 months relative to the expected trajectory (P = 0.012), reflecting improvements in VO₂ max (R² = 0.27, P = 0.002) but not body composition changes. Notably, GrimAge changes strongly correlated with fluctuations in leukocyte composition, particularly neutrophil fraction (R² = 0.74, P < 0.001). Adjusting for leukocyte composition improved consistency in GrimAge changes, aligning them with additional intervention outcomes and explaining up to 81% of variance. These findings demonstrate that GrimAge is responsive to short-term endurance training, serving as a meaningful biomarker of improved cardiorespiratory fitness, while also capturing immune system variability. This study supports the use of GrimAge in evaluating longevity interventions and highlights the importance of accounting for leukocyte composition in epigenetic aging research.

  Study EGAS00001008221

• 3.5KJPNv2, an allele frequency panel of 3,552 Japanese individuals

  In the Tohoku Medical Megabank Project, we have conducted whole-genome sequencing of nearly 4,000 individuals from a Japanese population, and constructed an allele frequency panel of 3,552 individuals (3.5KJPNv2) after removing genetically related individuals. The 3.5KJPNv2 was constructed by using a standard pipeline including the 1KGP and gnomAD algorithms to reduce technical biases and to allow comparisons to other populations. The 3.5KJPNv2 includes variants in chromosome X and mitochondrial genome as well as autosome. The submitter has changed the access level of this study from controlled-access [Type I] to un-restricted access since 11th, January, 2019. The un-restricted access data ?hum0015.v3.3.5kjpnv2.v1? are available at the NBDC site: https://humandbs.biosciencedbc.jp/en/hum0015-v3. This study does not contain any controlled-access dataset.

  Study JGAS000159

• Whole genome sequencing data for 10 hepatocellular carcinomas (HCC) and matched non-tumor liver tissues + optical mapping data for 4 HCC and 3 matched non-tumor liver tissues.

  Oncogene activation leads to replication stress and promotes genomic instability. Here we combine optical mapping and whole genome sequencing to explore in-depth the nature of structural variants (SVs) induced by replication stress in cyclin-activated hepatocellular carcinomas (CCN-HCC). In addition to classical tandem duplications, CCN-HCC display frequent intra- and inter-chromosomal templated insertion cycles (TIC) likely resulting from template switching events. Template switching preferentially involves active topologically associated domains that are close in the 3D genome organization. Template sizes depend on the type of cyclin activation and are coordinated within each TIC. Replication stress induces continuous accumulation of SVs during CCN-HCC progression, fostering the acquisition of new driver alterations and large-scale copy-number changes at TIC borders. Together, this analysis sheds light on the mechanisms, dynamics and consequences of SV accumulation in tumors with oncogene-induced replication stress.

  Study EGAS00001005629

• Somatic mutation and selection at epidemiological scale - TwinsUK_TargetedNanoSeq_Blood

  Utilising Targeted NanoSeq, we hope to explore the driver landscape in unprecedented detail in donors from TwinsUK. These donors have paired buccal swabs and data from this will help contextualise that work. As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 5 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

  Dataset EGAD00001015619

• Phylogenetic Analyses of Melanoma Reveal Complex Patterns of Metastatic Dissemination

  Subpopulations of cells in a primary melanoma can disseminate and establish metastases. Still, the precise ancestral relationship between primary tumors and their metastases is not well understood. Using whole-exome sequencing (for discovery) and targeted sequencing (for validation), we analyzed mutation patterns of primary melanomas and two or more metastases in each of 8 patients to determine their phylogenetic relationships, profiling a total of 31 total tumors. The resulting data show that in 6 of 8 cases, genetically unique cell populations in the primary metastasized in parallel to distinct anatomic sites, rather than sequentially. These data also indicate that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct.

  Study phs000941

• Tumor-specific expression of let-7i and miR-192 is associated with resistance to cisplatin-based chemoradiotherapy in patients with larynx and hypopharynx cancer

  Background: The majority of patients with locally advanced larynx or hypopharynx squamous cell carcinoma are treated with organ preserving chemoradiotherapy (CRT). Clinical outcome following CRT varies greatly. We hypothesized tumor microRNA (miRNA) expression is predictive for outcome following CRT. Methods: Next-generation sequencing (NGS) miRNA profiling was performed on 37 formalin fixed paraffin embedded (FFPE) tumor samples. Patients with a recurrence free survival (RFS) of less than 2 years (“poor outcome”) and patients without recurrence within 2 years (“good outcome”) were compared by differential expression analysis. Tumor-specific miRNAs were selected based on normal mucosa miRNA expression data from The Cancer Genome Atlas database. A model was constructed to predict outcome using group-regularized penalized logistic ridge regression. Candidate miRNAs were validated in the initial sample set by RT-qPCR as well as in 46 additional tumor samples.Results: 1,938 known mature miRNAs were detected. Thirteen miRNAs were differentially expressed (p<0.05, FDR<0.1) according to outcome group. Initial class prediction in the NGS cohort (n=37) resulted in a model combining five miRNAs and disease stage, able to predict CRT outcome with an area under the curve (AUC) of 0.82. In the RT-qPCR cohort (n=83), 25 patients (30%) experienced early recurrence (median RFS 8 months; median follow-up 42 months). Class prediction resulted in a model combining let-7i-5p and miR-192-5p and disease stage, able to discriminate with an AUC of 0.80 patients with good versus poor clinical outcome.Conclusion: The combined miRNA expression and disease stage prediction model is superior to using either factor alone. ¬¬¬This study indicates NGS miRNA profiling using FFPE specimens is feasible, resulting in clinically relevant biomarkers.

  Study EGAS00001004001

• Chronic Renal Insufficiency Cohort (CRIC) - GWAS

  The Chronic Renal Insufficiency Cohort (CRIC study) was established in 2001 by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) to improve the understanding of the relationship between chronic kidney disease and cardiovascular disease. The goals of the CRIC Study are to examine risk factors for progression of chronic kidney disease and cardiovascular disease among patients with chronic kidney disease and to develop predictive models to identify high-risk subgroups, informing future treatment trials and increasing application of available preventive therapies. Data available at dbGaP include genotype data for 3527 participants released in version 1. Plasma metabolomics and plasma proteomics data will be available at dbGaP in "Chronic Renal Insufficiency Cohort (CRIC) Study Metabolomics and Proteomics". Additional phenotypic, clinical, and outcomes data are available at the NIDDK Central Repository and can be linked to data available at dbGaP. More than 330 manuscripts have been published, reporting on the effects of a broad range of risk factors (from molecular biomarkers of disease pathways to clinical, demographic, and behavioral characteristics) on the progression of CKD and other health consequences. The full CRIC bibliography can be found at http://cristudy.org/Chronic-Kidney-Disease/Chronic-Renal-Insufficiency-Cohort-Study/bibliography-2024-2023.

  Study phs000524

• Genomic landscapes of endometrioid and mucinous ovarian cancers and morphologically similar tumor types

  While endometrioid and mucinous ovarian cancers represent nearly a quarter of ovarian cancers, their molecular characteristics and pathologic origins are poorly understood. To characterize the genomic and epigenomic alterations of these ovarian cancer subtypes and evaluate links to morphologically similar tumors from other sites, we performed sequence, copy number, mutation signature, rearrangement, and methylation analyses from tumor samples and matched normal tissues of 133 patients. These analyses included patients with ovarian endometrioid (n=44), ovarian mucinous (n=43), uterine endometrial (n=15), and gastrointestinal mucinous cancers (n=31). In addition to identifying genes previously known to be involved in these tumors, we identified alterations in RAD51C, NOTCH4, SMARCA1/4 and JAK1 in ovarian endometrioid, ESR1 in uterine endometrioid, and SMARCA4 in ovarian mucinous cancers. Whole genome sequencing revealed rearrangements involving PTEN, NF1, and NF2 in ovarian endometrioid tumors, and NF1 and MED1 in ovarian mucinous cancers. The number of alterations and affected genes in ovarian and uterine endometrioid cancers were similar as were genome-wide methylation profiles, suggesting that these tumors may have a similar tissue of origin. By contrast, methylation patterns in ovarian mucinous cancers were more similar to other gastrointestinal mucinous cancers, including mucinous cancers of the stomach, colon, and pancreas. These analyses provide insights into the genomic landscapes and origins of mucinous and endometrioid ovarian carcinomas, providing new avenues for early clinical intervention and management of patients with these cancers.

  Study EGAS50000000523

• The International Consortium for Prostate Cancer Genetics Genome Wide Association Study of Familial Prostate Cancer

  Initially, the ICPCG focused largely on high-risk prostate cancer pedigrees using linkage analysis. However, association studies have also been informative to find prostate cancer susceptibility variants in the genome. We hypothesize that genome-wide (GW) association studies of familial cases of prostate cancer will have the power to identify rarer and perhaps less penetrant risk variants associated with prostate cancer than have been identified to date. Our approach will be to examine evidence for association in selected, independent cases from high-risk pedigrees; we hypothesize that they represent a more homogeneous set of cases with potentially different associations. Use of the 5M plus exome SNP platform will allow us to include in our search more rare variants in our search than have ever been investigated for prostate cancer. Aim 1. Identify a set of independent prostate cancer cases selected from ICPCG high-risk prostate cancer pedigrees that have 3 or more related prostate cancer cases and have an average age at diagnosis ≤ 75 years. Identify appropriate matched controls from participating ICPCG groups/ populations. Aim 2. Perform GW SNP genotyping with the Illumina 5M plus exome SNP set on the set of independent prostate cancer cases and controls described in Aim 1. Aim 3. Perform association analyses appropriately matching controls for different ICPCG populations and groups. There will be a two-stage design for confirmation. Aim 4. Test reported associations using the extensive sample set available to us by collaboration with the PRACTICAL consortium that has access to 50 000 DNA samples from 34 groups internationally (over 7,000 of whom are positive for prostate cancer family history).

  Study phs000733

• A_study_of_the_genetic_basis_of_evation_by_Acute_Myeloid_Leukaemia_of_Graft_vs_Leukaemia_effects_after_allogeneic_bone_marrow_transplantation

  Acute myeloid leukaemia (AML) is an aggressive and molecularly diverse disease with a poor overall survival of 20-25%. With an annual incidence of 2.9 per 100,000, AML is currently the commonest myeloid malignancy in Europe, yet the two main therapeutic options for this disease, anthracyclines and purine analogues, have remained unchanged for over 20 years. Currently patients are stratified at diagnosis according to a series of clinicopathological parameters (e.g. age, white cell count and presence/absence of previous clonal haematological disease) and molecular markers (e.g. chromosomal translocations/deletions, aneuploidy and mutations in genes such as FLT3 and NPM1). Patients with adverse prognostic features, whose prognosis is particularly poor (e.g. <15% long-term survival) are offered treatment with allogeneic bone marrow transplantation (allo-BMT) if a sibling or unrelated donor is available. This can significantly improve survival (e.g. up to 40% long-term survival in some contexts), albeit at the expense of significant toxicity and transplant-related mortality (TRM). Allo-BMT is thought to work in part by allowing the delivery of large doses of chemotherapy followed by haemopoietic "rescue" with donor haemopoietic stem cells (haemopoietic failure would otherwise ensue). However, potentially the most potent effect of allo-BMT is the cytotoxic effect of donor lymphocytes against AML blasts, a phenomenon known as graft-vs-leukaemia (GVL) effect. Increasingly, transplants using reduced chemotherapy intensity (mini-allografts) are being used that partially circumvent the toxicity from chemotherapy and rely on GVL to effect cure. Nevertheless, AML relapse after allo-BMT still occurs at a significant rate of up to 80% depending on the type of transplant. There is accumulating evidence that genetic events in residual leukaemic cells enable them to evade immunodetection and therefore survive the GVL effect and expand to cause relapse. The most striking example of this is the loss of HLA antigens after transplants in which donor and recipient are not fully HLA-matched. In these cases, the leukaemia "deletes" the genomic region containing the disparate HLA antigen which was preferentially targeted as "foreign" by the GVL effect. However, the genetic basis of immune evasion in the majority of transplants, which are fully HLA matched, is not known. One possibility is that loss of genes coding for antigens outside the HLA locus but which are also targets of GVL may operate, alternatively genetic events that affect processes downstream of immunological cytotoxicity may be responsible.The identification of genetic events that mediate immune evasion would not only facilitate the understanding of this process but can help plan therapeutic interventions that improve the outcomes of allogeneic transplantation for AML and other disorders. We intend to study this by conducting exome sequencing on 6 cases of AMLs from patients that attend my clinic at Addenbrooke's hospital and have relapsed after allogeneic transplantation. Samples from AML diagnosis, remission/normal and AML relapse (total n=18) will be studied to identify somatic mutations in the primary AML and those acquired by the relapsed clone. The 18 samples will also be studied by array CGH to detect regions of genomic amplification or deletion.

  Study EGAS00001000145

• Whole-genome bisulfite sequencing for high-grade glioma

  We conducted whole-genome bisulfite sequencing to delineate base-resolution methylomes of gliomas harboring G34R mutation as well as those harboring K27M and no mutations in H3F3A. Comparative analysis of these three glioma subgroups revealed that G34 subgroup exhibited lower global methylation levels, comparable CpG island (CGI) methylation levels, and compromised hypermethylation of telomere-proximal CGIs, compared to the other two subgroups. Genomic regions specifically hypermethylated in G34 subgroup were enriched for CGIs. CGIs with G34V-mutated histone H3.3 in the glioma cell line KNS-42 were hypermethylated compared to those without it, suggesting a correlation between G34-mutated histone H3.3 in CGI hypermethylation.

  Study JGAS000197

• Single Cell RNA-Seq Reveals Malignant and Stromal Programs Associated with Metastasis in Head and Neck Cancer

  This study of head and neck cancer aimed to profile individual malignant, stromal, and immune cells in treatment-naive oral cavity squamous cell carcinoma, with or without matched metastatic cervical lymph nodes. Clinical and pathologic information was collected on all patients, in addition to a fresh biopsy sample from the primary tumor and/or metastatic lymph node at the time of initial surgery. Biopsy specimens were processed for single cell RNA-seq (scRNA-seq) and/or whole exome sequencing (WES). A total of ~6,000 single cells from 18 participants were included in the final dataset. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). One of the top scoring genes in this program was TGFβ-induced (TGFBI), implicating the classic EMT regulator TGFβ. Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined Head and Neck Squamous Cell Carcinoma (HNSCC) subtypes by their malignant and stromal composition, and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.

  Study phs001474

• Whole Tumor spatial heterogeneity in metastatic melanoma

  Heterogeneous inter-tumoral responses, sustained periods of apparent clinical benefit despite lack of objective response to various therapies, and even spontaneous remission are well known within a subpopulation of advanced melanoma patients. The molecular and cellular dynamics facilitating long-term survival remain poorly defined, particularly in the current era ofexposure to multiple potentially active therapies. We studied an exceptional case of long-term survival in a patient with non-responding metastatic melanoma in order to characterize the clonal and microenvironmental factors.We performed immunogenomic analysis of 3 metachronous tumors, and of 67 intratumor sub-regions of one metastatic lesion, usingwhole exome sequencing, RNA-sequencing, immunohistochemistry, and T cell receptor sequencing. Longitudinal analysesidentified mutations in severalknownresistance genes affecting distinctmetastases. Intra-tumoral immune signatures revealed spatially-distinct pockets of immune activation and suppression throughout the metastasis. A specific T cell VBeta CDR3 rearrangement was identified as both dominant and recurrent not only across multiple spatial points within a single tumor mass, but also across metachronous tumors spanning the patient’s disease course. Immunophenotyping of this T cell population with single-cell sequencingsuggestedrepeatedT-cell priming events leading to the persistence of both activated and exhausted T cells bearing this same TCR-Beta at any given time.Our findings highlight genomic and immune heterogeneityin metastatic disease, extending to the intra-tumoral leveland provide a rationale for integrative spatiotemporal analysis of metastatic lesions in the context of immune checkpoint blockade.

  Study EGAS00001003292

• National Institute on Alcohol Abuse and Alcoholism (NIAAA) Postmortem Prefrontal Cortex eQTL and mQTL Study

  Mapping expression and methylation quantitative trait loci (eQTLs and mQTLs) using genome-wide genotype, transcriptome, and DNA methylome data can provide an unbiased approach to identify novel functional variants. One critical issue of the eQTL/mQTL analysis is that the role of genetic variants in regulating gene expression (or DNA methylation) can be tissue- or cell-specific. To unravel causal variants from disease-associated loci, it would be necessary to map eQTLs and mQTLs in both patients and controls. Those eQTLs and mQTLs in patients are more likely to be causal variants for the disease. Identification of disease- and tissue-specific eQTLs and mQTLs will help disentangle the role of the specific tissue in disease development as well. In the present study, we mapped eQTLs and mQTLs in postmortem prefrontal cortex of patients with alcoholism or alcohol use disorder (AUD) and matched control subjects by integrative analyses of genome-wide SNP genotype, mRNA transcriptome, and DNA methylome data. As AUD is comorbid with schizophrenia (SCZ), bipolar disorder (BIP), major depressive disorder (MDD), and attention deficit/hyperactivity disorder (ADHD), we further examined the co-localization of PFC eQTLs/mQTLs and GWAS-identified SNPs (mainly noncoding SNPs) that were associated with AUD as well as comorbid SCZ, BIP, MDD, and ADHD. Our study demonstrated the enrichment of PFC eQTLs/mQTLs in the above psychiatric disorder-associated genetic variants identified by genome-wide association studies (GWAS).

  Study phs001981

• PSCP_bisulphite analysis in hESCs

  Many studies over the past 10 years, culminating in the recent report of the International Stem Cell Initiative (ISCI, 2011) have shown that hPSC acquire genetic and epigenetic changes during their time in culture. Many of the genetic changes are non-random and recurrent, probably because they provide a selective growth advantage to the undifferentiated cells. Some are shared by embryonal carcinoma cells, the malignant counterparts of ES cells. The origins of these growth advantages are poorly understood, but may come from altered cell cycle dynamics, resistance to apoptosis or altered patterns of differentiation. Less is known about the nature and consequences of epigenetic changes, but it is likely that these similarly affect hPSC behaviour; e.g., enhanced expression of DLK1, an imprinted gene, is associated with altered hPSC growth (Enver et al 2005). Inevitably, these genetic and epigenetic changes will impact on our ability to use hPSC for regenerative medicine, either because malignant transformation of the undifferentiated cells or their differentiated derivatives to be used for transplantation compromises safety, or because they impede the function of those differentiated derivatives, or because they affect the efficiency with which the undifferentiated cells can be expanded and differentiated into desired cell types. Focusing initially upon the existing clinical grade hESC lines, later moving to iPSC, we will Consolidate and extend knowledge of the rate, type and functional impact of the genetic variations that occur during hPSC culture. We will use whole genome and exome sequencing as well as SNP arrays, together with clonal analysis and other cytogenetics techniques. Common changes will be compared with those found in the normal human population, at low frequency in the original cell population or observed during iPSC generation in the HIPSCI project currently based at the WTSI. These studies will provide a better understanding of the range of genetic changes that occur in hPSC beyond the CNVs already identified. In conjunction with cancer genome resources and expertise at WTSI, bioinformatic analyses of these hPSC data will allow us to assess potential impact on hPSC behaviour pertinent to applications in regenerative medicine, notably the likelihood that specific changes arising in undifferentiated PSC cultures may be associated with potential malignant transformation of differentiated progeny. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001002235

• PSCP_mutation analysis in hESCs

  Many studies over the past 10 years, culminating in the recent report of the International Stem Cell Initiative (ISCI, 2011) have shown that hPSC acquire genetic and epigenetic changes during their time in culture. Many of the genetic changes are non-random and recurrent, probably because they provide a selective growth advantage to the undifferentiated cells. Some are shared by embryonal carcinoma cells, the malignant counterparts of ES cells. The origins of these growth advantages are poorly understood, but may come from altered cell cycle dynamics, resistance to apoptosis or altered patterns of differentiation. Less is known about the nature and consequences of epigenetic changes, but it is likely that these similarly affect hPSC behaviour; e.g., enhanced expression of DLK1, an imprinted gene, is associated with altered hPSC growth (Enver et al 2005). Inevitably, these genetic and epigenetic changes will impact on our ability to use hPSC for regenerative medicine, either because malignant transformation of the undifferentiated cells or their differentiated derivatives to be used for transplantation compromises safety, or because they impede the function of those differentiated derivatives, or because they affect the efficiency with which the undifferentiated cells can be expanded and differentiated into desired cell types. Focusing initially upon the existing clinical grade hESC lines, later moving to iPSC, we will Consolidate and extend knowledge of the rate, type and functional impact of the genetic variations that occur during hPSC culture. We will use whole genome and exome sequencing as well as SNP arrays, together with clonal analysis and other cytogenetics techniques. Common changes will be compared with those found in the normal human population, at low frequency in the original cell population or observed during iPSC generation in the HIPSCI project currently based at the WTSI. These studies will provide a better understanding of the range of genetic changes that occur in hPSC beyond the CNVs already identified. In conjunction with cancer genome resources and expertise at WTSI, bioinformatic analyses of these hPSC data will allow us to assess potential impact on hPSC behaviour pertinent to applications in regenerative medicine, notably the likelihood that specific changes arising in undifferentiated PSC cultures may be associated with potential malignant transformation of differentiated progeny. This data is part of a pre-publication release. For information on the proper use of pre-publication data shred by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001002231

• Genome-Wide Analysis for Addiction Susceptibility Genes

  Genome wide analysis for addiction susceptibility genes is an affected sibling pair linkage study using subjects who were patients in methadone replacement treatment programs (MMTP). Such patients are highly addicted to opioids and usually to other addicting substances as well. For entry into the programs, patients had to be at least 18 years of age and had to satisfy DSM-IV criteria for opioid dependence. Despite their common substance use disorder diagnosis, patients enrolled in MMTPs generally have a heterogeneous mix of co-morbid psychiatric disorders including anti-social personality disorder, major depression and anxiety disorders, and often satisfy DSM-IV criteria of substance use disorders other than opioid dependence. Genetic analysis was carried out using genotyping data obtained from a 10K SNP array, and non-parametric linkage was assessed using MERLIN. This resulted in the identification of a linkage peak on 14q that overlapped the NRXN3 gene (neurexin 3), which was previously identified as a potential candidate gene for addiction, and subsequently identified as a target gene in other addiction studies and autism. In version 2 of this study, a text file containing 7704 SNPs with large allele frequency discrepancy as compared to 1000 Genomes is included. Users have the option to exlude these 7704 SNPs.

  Study phs001266

• Finnish_population_cohort_genotyping_B

  The FINRISK cohorts comprise the respondents of representative, cross-sectional populationsurveys that are carried out every 5 years since 1972, to assess the risk factors of chronicdiseases (e.g. CVD, diabetes, obesity, cancer) and health behavior in the working agepopulation, in 3-5 large study areas of Finland. DNA samples were collected in the followingsurvey years: 1987, 1992, 1997, 2002, 2007, and 2012. The MONICA and EHES (EU)procedures were applied in phenotype collection (cf. MORGAM) and a wide spectrum oflaboratory tests was carried out from serum and plasma samples. Background information onsocioeconomic status, medical history, diet, exercise, measured anthropometric measures,etc. was collected by questionnaires and during a clinical visit. Plasma/serum samples arestill available for the 2002-2012 cohorts. The cohort sizes are 6000-8800 per survey. Thecohorts have been followed up by linking them to the national hospital discharge register,causes-of-death register and cancer register.This project is an extension to previous efforts to build a catalogue of Finnish genome widedata on population-based Finsrisk samples with rich phenotypic characterisations and healthregistry link-up. These samples will extend the current Sequencing Initiative Suomi (SISu)samples with a combination of genotyping using Illumina HumanCoreExome array and SISu-based imputation. This will lead to high confidence common and low frequency variantcatalogue. The project will be funded by Aarno Palotie’s remaining faculty fundscomplemented by Finnish funding from FIMM.

  Study EGAS00001001047

• Foregut Microbiome in Development of Esophageal Adenocarcinoma

  The distal esophagus is an important anatomical area where gastric acid reflux can cause reflux esophagitis (RE), Barrett's esophagus (BE) (intestinal metaplasia), and esophageal adenocarcinoma (EA). The incidence of EA has increased 6-fold in the U.S. since the 1970s, parallel to a significant increase in the prevalence of gastroesophageal reflux diseases (GERD). Although specific host factors might predispose one to disease risk, such a rapid increase in incidence must be predominantly environmental. The cause remains unknown. Our hypothesis is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in the GERD sequence. We will conduct a case control study to characterize the microbiome in every stage of the GERD sequence as well as analyze the trend in changes in the microbiome along disease progression toward EA. Specific Aim 1. To conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence, by a 16S rRNA gene survey. We will analyze samples of the foregut microbiome at three anatomic loci: mouth, distal esophagus, and gastric corpus. Changes of the microbiota in the distal esophagus will be correlated with the phenotypes. Spatial relationship between the esophageal microbiota and upstream (mouth) and downstream (stomach) foregut microbiotas as well as temporal stability of the microbiome-disease association will also be examined. Specific Aim 2. To define distal esophageal metagenome and demonstrate its association with GERD sequence, by shotgun metagenomic analysis. We will first classify samples of the metagenome into metagenotypes by between-sample k-mer distance and correlate the metagenotypes with the four phenotypes. Subsequent detailed analyses will include pathway-disease and gene-disease associations. DNA viruses and fungi, if identified, also will be correlated with the phenotypes. A significant association between the foregut microbiome composition and GERD sequence, if demonstrated, will be the first step for eventually testing the causal hypothesis that an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microbial ecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiome through use of antibiotics, probiotics, or prebiotics. Causative therapy for GERD could prevent its progression and reverse the current trend of increasing incidence of EA.

  Study phs000260

• Kids First: The Genomic Basis of Structural Birth Defects Associated with Chromosome 18 Copy Number Changes

  Chromosome abnormalities are a common cause of structural birth defects. Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions.However, because these genomic copy number changes involve multiple genes and because most of these conditions are individually rare, defining the specific causative genes behind specific phenotypes has been a challenge. We met that challenge by spending the last 28 years enrolling and evaluating anyone with a chromosome 18 abnormality. The cohort now includes over 700 individuals with a wide variety of chromosome 18 copy number changes (CNV), as well as their parents. Because the vast majority of these participants have individually unique CNVs, we have been able to perform extensive genotype-phenotype correlations resulting in 58 publications. Of the 263 genes on chromosome 18, 28 are linked to specific hemizygous phenotypes. However, most have low penetrance. Genomic sequence data could identify variants in the extant allele that are hypermorphic and compensate for hemizygosity, or are hypomorphic and exacerbate hemizygosity. Additionally, there are phenotypes within this cohort that are rare, or an extreme version of one of the more common phenotypes. Genomic sequence data could help discover new biallelic conditions by revealing functional sequence variants of the extant allele. In both of these cases, there could also be variants in other genes on other chromosomes that may be associated with the phenotype that confer susceptibility or resilience. Inclusion of this unique cohort in the Gabriella Miller Kids First Pediatric Research Program can advance the goals of the program in several ways. First, by adding known susceptibility loci to the existing Kids First cohorts for the structural birth defects that are also found in our cohort. Second, for those structural birth defects known to be polygenetic, this cohort has a single defined risk factor which can simplify the search for secondary factors. Third, these studies can also bring clarity to people with chromosome 18 conditions and help to make the genotype more accurately predict phenotype. This approach could be a model for understanding the many other rare chromosome abnormalities which collectively are a common cause of structural birth defects.

  Study phs002627

• NCI COVID-19 in Cancer Patients Study (NCCAPS): A Longitudinal Natural History Study

  NCCAPS is a longitudinal prospective cohort study designed to assess patient, disease and treatment factors associated with short- and long-term outcomes in patients with cancer who develop COVID-19. We also aimed to describe COVID-19 symptoms and treatments, and to describe disruptions in cancer treatment due to COVID-19. The study enrolled patients with cancer on active treatment or with a history of stem cell transplant or CAR-T cell therapy with new, active COVID-19, defined as being within 14 days of their first positive SARS-CoV-2 test. The study found that receipt of chemotherapy and baseline history of stroke, atrial fibrillation or pulmonary embolism were associated with a higher risk of hospitalization for COVID-19. Vaccination for SARS-CoV-2 was associated with a lower risk of hospitalization. Death due to COVID-19 was highest in patients with lymphoma, intermediate in those with acute leukemia and lung cancer, and lowest in those with other solid tumors and other hematologic cancers. Disruptions of cancer treatment were frequent in the first 30 days after SARS-CoV-2 infection.

  Study phs004178

• Deciphering molecular mechanisms underlying hematological malignancies and development of novel therapeutic approaches

  We aim to identify epigenomic features dysregulated in hematological malignancies through epigenetic analyses of hematological malignant cells. We also perform RNA sequencing to profile tumor cell-specific transcriptomes and target gene sequencing to profile somatic gene mutations in tumor cells. Regarding identified epigenomic abnormalities, we perform further analysis to determine whether they could be good candidates to translate into therapy development. To this end, we will modulate the activity of targets by using their activators and inhibitors in vitro and establish xenograft mouse models of hematological malignancies and manipulate their activity in vivo. Through these studies, we aim to develop new therapeutic agents or modalities that lead to improved patients��� prognosis.

  Study JGAS000603

• RNAseq Iron-Treated iPSC-derived Microglia

  Iron accumulation in microglia has been observed in Alzheimer’s disease and other neurodegenerative disorders and is thought to contribute to disease progression through various mechanisms including neuroinflammation. To study the interaction between iron accumulation and inflammation, we treated human induced pluripotent stem cell-derived microglia (iPSC-MG) with an increasing concentration of iron, in combination with inflammatory stimuli such as interferon gamma and amyloid β, and performed RNA sequencing.

  Study EGAS00001006112

• Heart and Vascular Health Study (HVH)

  Objectives The Heart and Vascular Health Study (HVH) is a case-control study of risk factors for the development of myocardial infarction (MI), stroke, venous thrombosis (VT), and atrial fibrillation (AF). The study setting is Group Health, an integrated health care delivery system in Washington State. Background The HVH originated in 1988 with the examination of risk factors for MI. Over the ensuing years, the study has been funded by a series of grants, which have added case subjects with stroke, VT, and AF, and used a common control group. Study aims have focused on the associations of medication use with cardiovascular events. Starting in 1997, the study aims expanded to include genetic associations with cardiovascular disease. Participants recruited in 2009 or later and who provided blood samples for genetic analysis were asked for consent to deposit genetic and phenotype data in dbGaP. Design As part of the HVH study, case subjects were identified by searching for ICD-9 codes consistent with MI, stroke, VT, or AF, and medical records were reviewed to confirm the diagnosis. Control subjects were identified at random from the Group Health enrollment and were matched to MI cases. All subjects have an index date. For cases, the index date was assigned as the date that the cardiovascular event (MI, stroke, VT, or AF) came to clinical attention. For controls, the index date was a random date within the range of the case index dates. For both cases and controls, information was collected from the inpatient and outpatient medical record, by telephone interview with consenting survivors, and from the Group Health pharmacy and laboratory databases. Consenting participants provided a blood specimen. Genetic Research Genetic factors underlying cardiovascular disease are studied using DNA isolated from the blood samples.

  Study phs001013

• Kids First: Congenital Heart Defects and Laterality Birth Defects

  Laterality defects occur in approximately 1:10,000 newborns and are associated with a range of structural birth defects and abnormalities of organ positioning. Gut malrotation, biliary atresia, asplenia or polysplenia, complex cardiovascular malformations, and midline defects such as neural tube defects, vertebral anomalies and rib fusions are found in various combinations in patients with laterality defects. In addition, a subset of laterality defects caused by abnormalities of cilia position or function are associated with additional medical problems such as chronic sinusitis and bronchiectasis that require specific preventive care; however these patients frequently are undiagnosed until late in disease course. The goal of this project is to elucidate the genetic architecture of laterality disorders in order to inform medical management and risk stratification and to prevent complications. Laterality disorders are genetically heterogeneous and we and others have previously identified single nucleotide variants inherited in an X-linked or autosomal recessive manner as explanations for a minority of cases. In addition, we have demonstrated copy number variants (CNVs) as a mechanism of disease that requires additional investigation. We hypothesize that the majority of cases result from complex genetic inheritance. We propose to investigate this hypothesis using a multifaceted analysis approach in our extremely well phenotyped cohort of 538 probands with laterality disorders. Nested within this cohort are 105 trios who have not had previous sequencing, probands who have had exome sequencing and are excellent candidates for gene discovery via whole genome sequencing (WGS), and families with multiple affected family members for family-based analysis. All trios will be analyzed by transmission disequilibrium test (TDT) including rare variant TDT. De novo mutations will also be identified from trios for potential gene discovery. Using all probands, we will identify the prevalence of pathogenic CNVs. In addition, we will perform burden analyses to identify genes, gene interactions, and pathways important for susceptibility to laterality disorders. Finally, our rare families with multiple affected members will be studied using family based segregation analysis. This comprehensive genetic analysis in patients with laterality disorders is necessary to identify the appropriate clinical diagnostic testing for risk stratification, to elucidate underlying genetic architecture and facilitate novel gene discovery, and to provide essential knowledge about genes and pathways impacting the development of laterality disorders.

  Study phs002589

• IL-17B uses IL-17RA and IL-17RB to induce Type-2 inflammation from human lymphocytes

  IL-17 family cytokines are critical to host defense responses at cutaneous and mucosal surfaces. Whereas IL-17A, IL-17F, and IL-17C induce overlapping inflammatory cascades to promote neutrophil-mediated immunity, IL-17E/IL-25 drives type 2 immune pathways and eosinophil activity. Genetic and pharmacological studies reveal the significant contribution these cytokines play in antimicrobial and autoimmune mechanisms. However, little is known about the related family member, IL-17B, with contrasting reports of both pro- and anti-inflammatory function in rodents. We demonstrate that in the human immune system, IL-17B is functionally similar to IL-25 and elicits type 2 cytokine secretion from innate type 2 lymphocytes, NKT, and CD4+ CRTH2+ Th2 cells. Like IL-25, this activity is dependent on the IL-17RA and IL-17RB receptor subunits. Furthermore, IL-17B can augment IL-33–driven type 2 responses. These data position IL-17B as a novel component in the regulation of human type 2 immunity.

  Study EGAS50000000579

• Center for Common Disease Genomics [CCDG] - Cardiovascular: SWISS-AF/SWISS-AF-PVI/BEAT-AF

  This study is a part of NHGRI's Centers for Common Disease Genomics (CCDG), which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation (AF), congestive heart failure and type 2 diabetes. AF will affect between 6-12 million individuals in the US by 2050. AF is also associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1. Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules. Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOAF_FINAL_w_link.pdf Three collections were brought together to form Swiss atrial fibrillation cases: SWISS-AF, SWISS-AF-PVI, and BEAT-AF. SWISS-AF is a prospective observational, multicentric cohort study in Switzerland to increase our knowledge on structural brain damage and its changes over time in patients with atrial fibrillation. Overall, 2400 patients with documented atrial fibrillation aged >65 years will be included and followed on a yearly basis. SWISS-AF-PVI is a registry of patients with atrial fibrillation undergoing catheter-based ablation of atrial fibrillation (pulmonary vein isolation) to determine long-term success rates of catheter-based ablation of atrial fibrillation (pulmonary vein isolation) and to evaluate factors associated with long-term success of catheter-based ablation of atrial fibrillation (pulmonary vein isolation). BEAT-AF is a prospective observational, multicenter cohort study in Switzerland. Overall, 1550 patients with documented atrial fibrillation were enrolled in seven study centers. The main aim of this study is to investigate the therapy and the medical consequences of patients with atrial fibrillation. Samples from all three collections were sent to The Broad Institute of MIT and Harvard to generate genetic data using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array); all cases with atrial fibrillation.

  Study phs002242

• Spatial and temporal evolution of distal 10q deletion, a prognostically unfavorable event in diffuse low-grade gliomas

  Background: The disease course of patients with diffuse low-grade glioma is notoriously unpredictable. Temporal and spatially distinct samples may provide insight into the evolution of clinically relevant copy number aberrations (CNAs). The purpose of this study is to identify CNAs that are indicative of aggressive tumor behaviour and can thereby complement the prognostically favorable 1p/19q co-deletion. Results: Genome-wide, 50 base pair single-end, sequencing was performed to detect CNAs in a clinically well-characterized cohort of 98 formalin-fixed paraffin-embedded low-grade gliomas. CNAs are correlated with overall survival as an endpoint. Seventy-five additional samples from spatially distinct regions and paired recurrent tumors of the discovery cohort were analysed to interrogate the intratumoral heterogeneity and spatial evolution. Loss of 10q25.2-qter is a frequent subclonal event and significantly correlates with an unfavorable prognosis. A significant correlation is furthermore observed in a validation set of 126 and confirmation set of 184 patients. Loss of 10q25.2-qter arises in a longitudinal manner in paired recurrent tumor specimens, whereas the prognostically favorable 1p/ 19q co-deletion is the only CNA that is stable across spatial regions and recurrent tumors. Conclusions: CNAs in low-grade gliomas display extensive intratumoral heterogeneity. Distal loss of 10q is a late onset event and a marker for reduced overall survival in low-grade glioma patients. Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.

  Study EGAS00001000643

• CIDR, NCI, NIDA Sequencing of Targeted Genomic Regions Associated with Smoking

  This study includes samples from two projects: Collaborative Genetic Study of Nicotine Dependence (COGEND; PI: Laura Bierut) and Genetic Study of Nicotine Dependence in African Americans (AAND; PI: Laura Bierut and Eric Johnson). The majority of the COGEND subjects included in the current study overlap with the two datasets already available on dbGaP. GWAS data are available for COGEND subjects through the Study of Addiction: Genetics and Environment (SAGE), dbGaP study accession phs000092. It should be noted that the case definition in the SAGE study is DSM-IV alcohol dependence. GWAS data are available for additional COGEND subjects through The Genetic Architecture of Smoking and Smoking Cessation, dbGaP study accession phs000404. The overall goal of this project is to apply deep sequencing to key genomic regions associated with nicotine dependence in order to accelerate the discovery of variation in molecular pathways that govern the development of nicotine dependence. The sample includes unrelated cases and controls of European American and African American descent. Cases are defined by a commonly used definition of nicotine dependence, a current score of 4 or more (maximum score of 10) on the Fagerstrom Test for Nicotine Dependence (FTND). Control status is defined as an individual who smoked at least 100 cigarettes during their lifetime, yet never became dependent (lifetime FTND<2). By selecting controls who smoked cigarettes, we focus on those genetic effects that are specific to the development of nicotine dependence. COGEND: COGEND was initiated in 2001 as a three-part program project grant funded through the National Cancer Institute (NCI; PI: Laura Bierut). The three projects included a study of the familial transmission of nicotine dependence, a genetic study of nicotine dependence, and a study of the relationship of nicotine dependence with nicotine metabolism. The primary goal was to detect, localize, and characterize genes that predispose or protect an individual with respect to heavy tobacco consumption, nicotine dependence, and related phenotypes and to integrate these findings with the family transmission and nicotine metabolism findings. The primary design was a community based case-control study. Nicotine dependent cases and non-dependent, smoking controls were identified and recruited from Detroit and St. Louis. More than 54,000 subjects aged 25-44 years were screened by telephone; more than 3,100 subjects were personally interviewed; and more than 2,900 subjects donated blood samples for genetic studies. AAND: AAND was initiated in 2009 to identify and characterize genetic determinants of nicotine dependence in a large African American population. Community-based recruitment of approximately 100,000 people was conducted to ascertain 1,000 African American nicotine dependent cases and 1,000 African American non-dependent, smoking controls. All subjects were between the ages of 25-44. Subjects were screened by telephone; if they qualified as a case or control, they completed the same interview that was used in COGEND and donated a blood sample. Both studies (COGEND and AAND) included measures of basic socio-demographic variables, including age, sex, race/ethnicity, family income, and educational attainment using the Semi-Structured Assessment for the Genetics of Nicotine Dependence. Information on nicotine dependence, as assessed by the Fagerstrom Test for Nicotine Dependence (FTND) is available for all subjects. In addition, participants also completed the Nicotine Dependence Syndrome Scale (NDSS; Shiffman et al., 2004) and the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68; Piper et al, 2004). All subjects were assessed in person by trained research assistants.

  Study phs000813

• Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma

  Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the "Deutsche Studiengruppe Multiples Myelom". Subsequently, we correlated the detected mutations with common cytogenetic alterations and clinical parameters. We identified 11 novel non-synonymous SNVs or rare patient-specific SNPs, not listed in the SNP databases 1000 genomes and dbSNP, in 10 primary MM cases. The mutations predominantly affected the tyrosine-kinase and ligand-binding domains and no correlation with cytogenetic parameters was found. Interestingly, however, patients with RTK-mutations, specifically those with rare patient-specific SNPs, showed a significant lower overall, event-free and progression-free survival. This indicates that RTK SNVs and rare patient-specific RTK SNPs are of prognostic relevance and suggests that MM patients with RTK-mutations could potentially profit from treatment with RTK-inhibitors.

  Study EGAS00001001665

• Epigenomic atlas of organoid development

  To investigfate the epigenomic basis of fate decisions in the central nerveous system, we recorded a epigenomic timecourse of human brain organoid development using Cut&Tag with paired scRNA-seq. We further performed perturbation experiment inhibiting EED and profiled the response with scRNA-seq and Cut&Tag. Finally, we profiled a sample of the developing human brain using multiome sequencing and Cut&Tag. In our study, we uncover epigenomic switches during brain region diversification and show that epigenetic activation precedes gene expression during neurogenesis in organoids and in primary tissue. Lastly, we show that transcriptional repression by H3K27me3 is required to stabilize neuroectoderm induction from pluripotency.

  Study EGAS50000000155

• A Population Genomics Study Using a Disease-Targeted Cell model: Integration of

  The common genetic variants associated with complex traits typically lie in non-coding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs were tested for cis-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus. The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies. Reprinted from Grundberg E, Kwan T, Ge B et al., Genome Res Nov 2009, with permission from Genome Research, Cold Spring Harbor Press, PMID:19654370.

  Study phs000225

• Genomic Heterogeneity and the Small Renal Mass

  Tumor heterogeneity is believed to represent a barrier to pre-operative genomic characterization in kidney cancer. Previous studies of heterogeneity in clear cell renal cell carcinoma (ccRCC) evaluated only large and metastatic tumors. In small renal tumors in which multiple biopsies are not feasible, the extent of heterogeneity remains unknown. In this study, we evaluated how the extent of genomic heterogeneity in small and large ccRCC. A total of 23 small (<4cm ) and 24 large (>7cm ) ccRCC had 3 regions sampled for evaluation of copy number, clear-cell A/clear-cell B (ccA/ccB) classification, and cell cycle progression (CCP) score. Small tumors have less genomic complexity and significantly fewer subclonal events. Pre-treatment genomic characterization based on a single biopsy in small ccRCC can provide insight into biologic potential to make clinical decisions.

  Study EGAS00001002919

• Etiology of congenital thyroid dysfunction in Down Syndrome: a multi-omics investigation

  The goal of this study was to investigate dfiferences in the thyroid DNA methylome and transcriptome between fetuses with Down syndrome and fetuses with no genetic/developmental abnormality.

  Study EGAS50000000264

• Transcriptional characterization of human innate lymphoid cells (ILCs) and natural killer (NK) cells from fresh umbilical cord blood

  The heterogenicity of cord blood ILCs (ILC1, ILC2, ILC3) and NK cells in humans has so far not been assessed. In this study, we sorted from fresh cord blood the respective cell types from 3 donors and performed single-cell transcriptome analysis. To achieve high resoluation, each sorted population was labelled individually via multiplexing antibodies and subsequent Abseq staining before pooling. To determine single-cell transcriptomes the BD Rhapsody pipeline was performed. This is the first data set to characterize human ILCs and NK cells at such depth.

  Study EGAS50000001204

• Panbody_nanoseq

  Different cell types within the human body are subject to different endogenous and exogenous exposures which may result in distinct patterns of mutagenesis. In non-clonal tissues, it is difficult to assess these mutational patterns, including the rate at which they occur. This study will examine the mutational rates and signatures operating across a wide range of normal tissues using the nanoseq technology to reliably call variants, irrespective of their clonal composition. Each cell type will be enriched for using laser capture microdissection. This will serve as a reference against which future work on benign and malignant disease entities can be compared.

  Study EGAS00001005521

• AML FLT3 TCR study

  We identified a T-cell receptor (TCR) reactive to the recurrent FLT3 D835Y mutation in the tyrosine-kinase domain frequently expressed in acute myeloid leukemia (AML). To validate the TCRs' elimination efficacy of leukemic cells, we transplanted human AML cells with FLT3 D835Y mutation into NSG-SGM3 mice and treated either with TCR FLT3 D835Y redirected T cells, or control TCR (TCR 1G4). After treatment, we performed flow sorting of human AML cells from the mice (mCD45-hCD45+hCD3-hCD19-) and compared to primary AML blasts (hCD3-hCD19-) and primary T cells (hCD3+hCD8+orhCD4+hCD19-hCD33-) by whole-exome sequencing.

  Study EGAS00001007467

• Single cell phenotypic profiling of 27 DLBCL cases reveals marked inter- and intra-tumoral heterogeneity

  Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and is notorious for its clinical heterogeneity. Patient outcomes can be predicted by cell-of-origin (COO) classification, demonstrating that the underlying transcriptional signature of malignant B-cells informs biological behavior in the context of standard combination chemotherapy regimens. In the current study, we used mass cytometry (CyTOF) to examine tumor phenotypes at the protein level with single cell resolution in a collection of 27 diagnostic DLBCL biopsy specimens from treatment naïve patients. We found that malignant B-cells from each patient occupied unique regions in 37-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Interestingly, variable MHC class II expression was found to be the greatest contributor to phenotypic diversity. Within individual tumors, a subset of cases showed multiple phenotypic subpopulations, and in one case we were able to demonstrate direct correspondence between protein-level phenotypic subsets and DNA mutation-defined subclones. In summary, CyTOF analysis can resolve both inter- and intra-tumoral heterogeneity among primary samples, and reveals that each case of DLBCL is unique and may be comprised of multiple, genetically distinct subclones.

  Study EGAS00001003860

• Circulating tumor DNA dynamics reveal KRAS G12C mutation heterogeneity and response to treatment with the KRAS G12C inhibitor divarasib in solid tumors

  Purpose: To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study. Experimental design: Plasma samples were collected for serial ctDNA profiling at baseline (Cycle 1 Day 1 prior to treatment) and multiple on-treatment time points (Cycle 1 Day 15 and Cycle 3 Day 1). Results: KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non-small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as Cycle 1 Day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction. Conclusion: Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.

  Study EGAS50000000315

• Prematurity and Respiratory Outcomes Program (PROP) Core Database Protocol (PROP-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: The Prematurity and Respiratory Outcomes Program (PROP) was performed to identify suitable predictors of respiratory outcomes that may serve as surrogate endpoints in future trials of prevention and therapy of respiratory diseases in preterm infants.Background: Acute and chronic respiratory morbidities are common in premature births, and can pose significant risk to the infant's health, particularly during the first two years of life. One such condition is bronchopulmonary dysplasia (BPD) where infants require oxygen therapy due to abnormal repair and impaired lung development after acute lung injury. BPD poses a high mortality risk, even in infants that survive the initial hospitalization. Regardless of BPD diagnosis, preterm infants frequently return for medical care due to symptoms of post-prematurity respiratory disease (PRD), which includes intermittent or chronic wheezing, cough without cold, poor growth, apnea and cyanosis, and lower respiratory tract infections. Impaired lung function can persist into adulthood, contributing to chronic respiratory diseases including asthma and emphysema.However, at the time of the PROP study, there were no objective measures to predict which preterm infants would have persistent respiratory problems after discharge from the hospital. Furthermore, improved survival rates of premature infants and the high prevalence of lasting respiratory morbidities highlight the need for more comprehensive strategies to address both short-term and long-term respiratory complications. Thus, the Prematurity and Respiratory Outcomes Program (PROP) was formed to investigate multiple research hypotheses on the molecular mechanisms that contribute to respiratory disease risk of premature neonates over the first year of life. Specifically, PROP investigators hypothesized that in survivors of extreme prematurity to 36 weeks postmenstrual age (PMA), specific biologic, physiologic and clinical data obtained during the initial hospitalization will predict respiratory morbidity between discharge and 1 year corrected age. Participants: A total of 835 infants were enrolled.Design: PROP was a collaboratively developed multicenter prospective cohort study of very preterm infants from birth through the time of discharge from the NICU and up to one year corrected age.Clinical data included maternal and infant demographics, co-morbidities, and daily infant respiratory, nutritional, and medication data until discharge. These were prospectively collected from birth using medical record review and family interviews. After discharge, phone interviews were conducted with the infant's main caregiver at 3, 6, 9 and 12 months corrected age to assess domains of respiratory morbidity. At 6 and 12 months corrected age, a survey of environmental respiratory irritant exposures and an assessment for gastroesophageal reflux disease were also completed. A standardized physical exam was performed at 36-40 weeks PMA and again at one year corrected age. The exam focused on anthropometrics, vital signs, and respiratory system signs. At 34-41 weeks PMA and within one week of anticipated discharge based on physiologic stability, a set of non-invasive respiratory assessments were performed to assess physiologic biomarkers in infants that were not mechanically ventilated or receiving non-invasive positive pressure ventilation. Respiratory inductance plethysmography (RIP) was performed before and after inhaled albuterol to assess potential airway reactivity. During the RIP study, continuous pulse oximetry was performed during quiet sleep in order to analyze oxygen desaturations and apneas. Standardized oxygen requirement challenge tests were performed at about 36 weeks PMA, and at about 40 weeks PMA if the infant was still hospitalized and was not eligible for, or failed, the previous challenge. Failure was defined as SpO2 20 seconds at any point in the testing. Infants breathing ambient air or that passed the 36 week challenge test underwent a hypoxia challenge consisting of a 15-minute trial of FiO2 of 0.15. Failure was defined as SpO2 The primary outcome was respiratory morbidity, as measured by the presence or absence of substantial post-prematurity respiratory disease (PRD) up to one year corrected age. PRD was classified as a positive response in at least one of four morbidity domains during at least two separate parental interviews. The domains were respiratory medications, hospitalizations for cardiopulmonary cause, respiratory symptoms, and home technology dependence (oxygen, ventilator, or CPAP/BiPAP). Mortality from a respiratory cause was also incorporated.

  Study phs004117

• Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers

  Germline mutations in BRCA1 or BRCA2 exist in ~2-7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants with a pathologic complete response (pCR) rate of 53%. As nearly half of the patients treated did not have pCR, better strategies are needed to overcome treatment resistance. To this end, we conducted multi-omic analysis of 13 treatment naïve breast cancer tumors from patients that went on to receive single-agent neoadjuvant talazoparib. We looked for biomarkers that were predictive of response (assessed by residual cancer burden) after 6 months of therapy. We found that all resistant tumors exhibited either the loss of SHLD2, expression of a hypoxia signature, or expression of a stem cell signature. These results indicate that the deep analysis of pre-treatment tumors can identify biomarkers that are predictive of response to talazoparib and potentially other PARP inhibitors, and provides a framework that will allow for better selection of patients for treatment, as well as a roadmap for the development of novel combination therapies to prevent emergence of resistance.

  Study EGAS00001005676

• Combined Metabolic Activators Reduces Liver Fat in Nonalcoholic Fatty Liver Disease Patients

  Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMA) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomics data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host-microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.

  Study EGAS00001005616

• Tissue-specific mutation accumulation in human adult stem cells during life

  Gradual accumulation of mutations in human adult stem cells during life is associated with various age-related diseases, including cancer. The number of stem cell divisions throughout life is believed to be a major determinant for mutation accumulation and could explain the extreme variation of cancer incidence across different organs. Yet, mutation patterns and rates of healthy adult stem cells remain unknown. Here, we determined genome-wide mutation patterns in primary adult stem cells of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years. We find that the number of mutations increases linearly with age up to several thousand mutations per cell at 87 years of age, while mutation spectra remain constant throughout life. Small intestine and colon stem cells have a 2-fold higher mutation rate per year compared with liver stem cells. These differences could be exclusively attributed to the mutagenic action of spontaneous deamination of cytosine residues and may reflect the high stem cell division rate in these tissues. The genomic distribution of somatic mutations is non-random and predominantly associated with DNA replication dynamics in the small intestine and colon, and with transcription in the liver. These results indicate that a stable balance between various mutagenic and DNA repair processes is maintained throughout life and that the activity of these processes in adult stem cells varies between tissues.

  Study EGAS00001001682

• Exome sequencing reveals pathogenic variants in known and novel candidate genes for severe sperm motility disorders

  STUDY QUESTION: What are the causative genetic variants in patients with male infertility due to severe sperm motility disorders? SUMMARY ANSWER: We identified high confidence disease-causing variants in multiple genes previously associated with severe sperm motility disorders in 9 out of 21 patients (43%). We also identified variants in novel candidate genes in 8 additional patients (38%). WHAT IS KNOWN ALREADY: Severe sperm motility disorders are a form of male infertility characterised by vital, but immotile sperm often in combination with a spectrum of structural abnormalities of the sperm flagellum. Examples of this spectrum of disorders include dysplasia of the fibrous sheath / multiple morphological abnormalities of the sperm flagella (DFS-MMAF) and severe forms of asthenozoospermia associated to non-specific structural defects. These disorders frequently recur in families and may include chronic respiratory disease. As such, genetic causes are suspected and many genes have recently been reported. Currently, depending on the clinical sub-categorisation, up to 50% of causality in patients with severe sperm motility disorders can be explained by pathogenic variants in at least 21 known genes. STUDY DESIGN, SIZE, DURATION: We performed exome sequencing in patients with severe sperm motility disorders from two different clinics, aiming to identify the underlying genetic defects and establishing a diagnostic yield in both. PARTICIPANTS/MATERIALS, SETTING, METHOD: Two groups of infertile men, one from Argentina (n= 9) and one from Australia (n=12), with clinically defined sperm motility disorders were included. All patients in the Argentine cohort were diagnosed with DFS-MMAF, based on transmission electron microscopy. Exome sequencing was performed in all 21 patients and variants with an allele frequency of <1% in the gnomAD population were prioritised and interpreted. MAIN RESULTS AND ROLE OF CHANCE: In 9/21 patients (43%), we identified pathogenic variants in known sperm motility disorder genes: CFAP43 (3 patients); CFAP44 (2 patients), QRICH2 (2 patients), DNAH1 (1 patient) and DNAH6 (1 patient). The diagnostic rate did not differ markedly between the Argentinian and the Australian cohort (44% and 42%, respectively). Furthermore, we identified patients with variants in the novel candidate sperm motility genes CFAP58, DNAH12, DRC1, MDC1, PACRG, SSPL2C and TPTE2. One patient presented with two possibly damaging variants in four candidate genes and it remains unclear which variants were responsible for the severe sperm motility defect in this patient. LIMITATIONS, REASONS FOR CAUTION: In this study, we described patients with potential bi-allelic variants in known and novel candidate genes for severe sperm motility disorders. Due to unavailability of parental DNA, we have not assessed de novo or maternally inherited dominant variants and could not phase the mutations to establish in all cases that the mutations occur on both alleles. WIDER IMPLICATIONS OF THE FINDINGS: Our results confirm an important role for five known genes for sperm motility and we demonstrate that exome sequencing is an effective method to diagnose patients with severe sperm motility defects (9/21 diagnosed; 43%). Furthermore, our analysis revealed seven novel candidate genes for severe sperm motility disorders. Genome-wide sequencing of additional patient cohorts and re-analysis of exome data of currently unsolved cases may reveal additional variants in these novel candidate genes.

  Study EGAS00001005018

• UK10K COHORT TWINSUK

  The UK10K project proposes a series of complementary genetic approaches to find new low-frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome-wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein-coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will directly analyse quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The TwinsUK samples will be part of the cohort study and will undergo whole genome sequencing. For further information with regard to this cohort please contact Brent Richards (brent.richards@kcl.ac.uk) or Nicole Soranzo (ns6@sanger.ac.uk).

  Study EGAS00001000108

• TRIGR collaboration between University of Helsinkin and Children's Mercy Research Institute

  DAC for collaborations between by the University of Helsinki and Children's Mercy Hospital, such as the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), used to study the evolving epigenomics of immune cells in type 1 diabetes at single nuclei resolution

  Dac EGAC50000000543

• NGS-based targeted exome sequencing of osteosarcoma

  The present study aimed to identify potential genomic markers for the prediction of chemosensitivity in patients with OS using a genomic approach.

  Study JGAS000282

• Elucidation of molecular mechanism of NAFLD-HCC

  We aimed to elucidate the interaction between cancer cells and immune cells in the tumor immune microenvironment of non-viral hepatocellular carcinoma.

  Study JGAS000311

• Neuropsychiatric Genetics of African Populations - Psychosis (NeuroGAP-Psychosis)

  The NeuroGAP-Psychosis study was conducted in South Africa, Kenya, Uganda and Ethiopia as a response to the lack of genetic diversity in large genomic studies of psychiatric disorders. The study aims to expand knowledge of the genetic and environmental risk factors for neuropsychiatric disorders in Africa through large-scale sample collection and analysis. The initial design is a case-control study in which cases are individuals with schizophrenia or bipolar disorder and controls are age, sex and ancestry matched with individuals from the same geographic location. Cases are patients who are recruited from clinical facilities, both inpatient and outpatient. Controls are people who present for treatment for general medical conditions at health facilities. Data on phenotype, mental disorders, history of physical health problems, substance use and history of past traumatic events was collected from all participants. Additionally, a sample of saliva is collected for DNA extraction. DNA samples were sent to the Broad Institute for genotyping using Illumina Infinium Global Screening Array.  

  Study phs002528

• BarcUVa-Seq (Biology of Colorectal Cancer Risk Enhancers)

  This study was designed to generate a cohort of normal colon mucosal biopsies from the "average risk" population. Its primary aims included the development of an RNA-seq dataset of normal colon mucosal biopsies across three colon regions (ascending, transverse and descending). Further, we aimed to provide plausible prioritization to genetic components of colorectal cancer risk by employing methods such as expression quantitative trait loci analysis. In doing so, we provide a novel reference dataset for the study of colon cancer risk in the healthy colon epithelium. RNA-seq was performed in batches on an Illumina HiSeq 2500 (batch 1-7) or NovaSeq 6000 (batch 8) on a total of 463 samples. Matched genotyping data was generated on the Illumina OncoArray BeadChip. Phasing was carried out using Minimac 3 and imputation was performed using The Haplotype Reference Consortium panel on the Michigan Imputation Server.Genotype and RNA-seq data will be made available in dbGaP.

  Study phs003338